mTORC1 and CK2 coordinate ternary and eIF4F complex assembly

Valentina Gandin; Laia Masvidal; Marie Cargnello; Laszlo Gyenis; Shannon McLaughlan; Yutian Cai; Clara Tenkerian; Masahiro Morita; Preetika Balanathan; Olivier Jean-Jean; Vuk Stambolic; Matthias Trost; Luc Furic; Louise Larose; Antonis E Koromilas; Katsura Asano; David Litchfield; Ola Larsson; Ivan Topisirovic

doi:10.1038/ncomms11127

mTORC1 and CK2 coordinate ternary and eIF4F complex assembly

Nat Commun. 2016 Apr 4:7:11127. doi: 10.1038/ncomms11127.

Authors

Valentina Gandin^{1

2

3

4}, Laia Masvidal⁵, Marie Cargnello^{1

2

3

4}, Laszlo Gyenis⁶, Shannon McLaughlan^{1

2

3

4}, Yutian Cai^{1

3}, Clara Tenkerian^{1

6}, Masahiro Morita³, Preetika Balanathan⁷, Olivier Jean-Jean⁸, Vuk Stambolic⁹, Matthias Trost¹⁰, Luc Furic⁷, Louise Larose¹¹, Antonis E Koromilas^{1

4

6}, Katsura Asano¹², David Litchfield⁶, Ola Larsson⁵, Ivan Topisirovic^{1

2

3

4}

Affiliations

¹ Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.
² Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.
³ Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.
⁴ Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.
⁵ Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm 171 76, Sweden.
⁶ Departments of Biochemistry and Oncology, Schulich School of Medicine &Dentistry, Western University, London, Ontario, Canada N6A 4L6.
⁷ Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Victoria 3168, Australia.
⁸ UPMC Univ Paris 06, CNRS-UMR8256, Paris 75005, France.
⁹ Princess Margaret Cancer Centre, University Health Network, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
¹⁰ MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Scotland DD1 5EH, UK.
¹¹ Department of Medicine, Polypeptide Laboratory, McGill University and The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada H3A 2B2.
¹² Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, Kansas 66506, USA.

Abstract

Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Casein Kinase II / genetics
Casein Kinase II / metabolism
Casein Kinase II / physiology*
Eukaryotic Initiation Factor-2 / metabolism
Eukaryotic Initiation Factor-2 / physiology
Eukaryotic Initiation Factor-4F / metabolism*
Gene Expression Regulation
HEK293 Cells
Humans
MCF-7 Cells
Mechanistic Target of Rapamycin Complex 1
Models, Genetic
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Multiprotein Complexes / physiology*
Oncogene Proteins / metabolism
Peptide Chain Initiation, Translational
Phosphorylation
Signal Transduction
Stress, Physiological
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
TOR Serine-Threonine Kinases / physiology*
Ternary Complex Factors / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factor-4F
Multiprotein Complexes
Nck protein
Oncogene Proteins
Ternary Complex Factors
Casein Kinase II
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding